Cancers and tumors can be controlled or eradicated by the immune system. The immune system includes several types of lymphoid and myeloid cells, e.g., monocytes, macrophages, dendritic cells (DCs), eosinophils, T cells, B cells, and neutrophils. These lymphoid and myeloid cells produce secreted signaling proteins known as cytokines. The cytokines include, e.g., interleukin-10 (IL-10), interferon-gamma (IFNgamma), IL-12, and IL-23. Immune response includes inflammation, i.e., the accumulation of immune cells systemically or in a particular location of the body. In response to an infective agent or foreign substance, immune cells secrete cytokines which, in turn, modulate immune cell proliferation, development, differentiation, or migration. Immune response can produce pathological consequences, e.g., when it involves excessive inflammation, as in the autoimmune disorders, whereas impaired immune response may result in cancer. Anti-tumor response by the immune system includes innate immunity, e.g., as mediated by macrophages, NK cells, and neutrophils, and adaptive immunity, e.g., as mediated by antigen presenting cells (APCs), T cells, and B cells (see, e.g., Abbas, et al. (eds.) (2000) Cellular and Molecular Immunology, W. B. Saunders Co., Philadelphia, Pa.; Oppenheim and Feldmann (eds.) (2001) Cytokine Reference, Academic Press, San Diego, Calif.; von Andrian and Mackay (2000) New Engl. J. Med. 343:1020-1034; Davidson and Diamond (2001) New Engl. J. Med. 345:340-350).
Methods of modulating immune response have been used in the treatment of cancers, e.g., melanoma. These methods include treatment with cytokines or anti-cytokine antibodies, such as IL-2, IL-12, tumor necrosis factor-alpha (TNFalpha), IFNgamma, granulocyte macrophage-colony stimulating factor (GM-CSF), and transforming growth factor (TGF). Where a cancer cell can produces a cytokine that enhance its own growth or its own survival, an anti-cytokine antibody may be an appropriate therapeutic agent (see, e.g., Ramirez-Montagut, et al. (2003) Oncogene 22:3180-3187; Braun, et al. (2000) J. Immunol. 164:4025-4031; Shaw, et al. (1998) J. Immunol. 161:2817-2824; Coussens and Werb (2002) Nature 420:860-867; Baxevanis, et al. (2000) J. Immunol. 164:3902-3912; Shimizu, et al. (1999) J. Immunol. 163:5211-5218; Belardelli and Ferrantini (2002) TRENDS Immunol. 23:201-208; Seki, et al. (2002) J. Immunol. 168:3484-3492; Casares, et al. (2003) J. Immunol. 171:5931-5939; Oft, et al. (2002) Nature Cell Biol. 4:487-494)
Interleukin-23 (IL-23) is a heterodimeric cytokine comprised of two subunits, i.e., p19 and p40. The p19 subunit is structurally related to IL-6, granulocyte-colony stimulating factor (G-CSF), and the p35 subunit of IL-12. The p40 subunit of IL-23 is also part of IL-12, a heterodimeric cytokine comprising p35 and p40. IL-23 mediates signaling by binding to a heterodimeric receptor, comprised of IL-23R and IL-12beta1. The IL-12beta1 subunit is shared by the IL-12 receptor, which is composed of IL-12beta1 and IL-12beta2. A number of early studies demonstrated that the physiological consequences of a genetic deficiency in p40 (p40 knockout mouse; p40KO mouse; p40−/− mouse) were different from, e.g., more severe or less severe, than those found in a p35KO mouse. Some of these results were eventually explained by the discovery of IL-23, and the finding that the p40KO prevents expression of both IL-12 and IL-23 (Oppmann, et al. (2000) Immunity 13:715-725; Wiekowski, et al. (2001) J. Immunol. 166:7563-7570; Parham, et al.(2002). J Immunol 168, 5699-708; Frucht (2002) Sci STKE 2002, E1-E3; Elkins, et al. (2002) Infection Immunity 70:1936-1948; Cua, et al. (2003) Nature 421:744-748).
Present methods for treating cancer are not completely effective, and cytokines, such as IL-12 or IFNgamma produce toxic side effects (see, e.g., Naylor and Hadden (2003) Int. Immunopharmacol. 3:1205-1215; Fernandez, et al. (1999) J. Immunol. 162:609-617). The present invention addresses these problems by providing methods of using agonists and antagonists of IL-23.